Hydrogen sulfide (H2S) is a colourless, flammable, water soluble gas, which is recognized exclusively as a toxic gas and environmental hazard. H2S has been reported as one of three important gasotransmitters together with nitric oxide (NO) and carbon oxide (CO), each of which take part in many physiological and pathological processes. H2S is also synthesized by mammalian tissues via two pyridoxal-5′-phosphatedependent enzymes responsible for metabolism of L-cysteine: cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). The endogenous H2S plays important role in regulating central and peripheral nervous system, cellular metabolism, immunological/inflammatory responses and various aspects of cardiovascular biology. In the cardiovascular system, the principal enzyme involved in the formation of H2S is CSE, expressed in vascular endothelial cells, smooth muscle cells as well as cardiac myocytes. While in central nervous system, the H2S was synthesized via CBS. In mammalian tissues and blood, the concentration of H2S is 1-160 mM under physiological conditions. Higher concentrations of H2S are present in the brain (50-160 mM) and blood (10-100 mM).
The role of hydrogen sulfide in inflammation, sepsis and burns has been studied recently. The physiological function of H2S is thought to reduce inflammation and protect tissues from injury (such as ulceration in the gastrointestinal tract), acting through several pathways. H2S can suppress leukocyte adherence to the vascular endothelium, leukocyte extravasation and consequent formation of oedema. It can substitute for oxygen in driving mitochondrial respiration, thereby attenuating oxidative-stress-related tissue injury. The ability of H2S to inhibit the activity of phosphodiesterases (PDEs) can contribute to its ability to relax vascular smooth muscle, resulting in enhanced blood flow. Resolution of inflammation can be enhanced by H2S through actions such as the promotion of neutrophil apoptosis, and driving macrophage differentiation towards the M2 (anti-inflammatory) phenotype. H2S can modulate the activity of a number of transcription factors: it inhibits nuclear factor-κB (NF-κB), leading to a reduced production of pro-inflammatory cytokines. Increased production of H2S occurs around sites of damage, such as around ulcers in the gastrointestinal tract, and can accelerate the healing of such damage via the stimulation of angiogenesis.
Angiogenesis is regulated by vascular endothelial growth factor (VEGF) and its signal transduction pathway, which is crucial in the initial stage of wound healing. It is reported that both endogenous and exogenous H2S can stimulate angiogenesis through PI-2K/Akt pathway and ATP-sensitive potassium channels. The endogenous angiogenic agent VEGF, which promotes elevations in intracellular calcium levels, may lead to H2S release that in turn contributes to VEGF-stimulated angiogenesis-related properties of ECs. Administration of H2S to endothelial cells in culture stimulates cell proliferation, migration and tube formation. In addition, administration of H2S to chicken chorioallantoic membranes stimulates blood vessel growth and branching. Furthermore, in vivo administration of H2S to mice stimulates angiogenesis and accelerate wound healing in type 2 diabetic mice.
H2S can protect endothelial cells and promote migration under hypoxic condition in HUVECs. These effects are partially associated with the preservation of mitochondrial function mediated by regulating the mitochondrial-dependent apoptotic pathway. A marked increase in gastric expression of the two key enzymes in hydrogen sulfide synthesis (CBS and CSE) and in hydrogen sulfide synthesis were detected in gastric ulcer in rat. Twice-daily treatment for a week with hydrogen sulfide donors significantly increased the extent of healing of gastric ulcers as compared to vehicle treatment. This study indicated that H2S is an endogenous regulator of wound healing, and enhancement of endogenous H2S synthesis or delivery of appropriate concentrations of H2S may have clinical utility in enhancing the healing of wounds, including gastrointestinal ulcers. H2S improves wound healing by restoration of EPC functions and activation of Ang-1 in type 2 diabetic mice. The findings indicated that an H2S donor may lead to novel therapeutic strategies for diabetic vascular complications and diabetic skin ulcerations. In addition, it is proposed that H2S acts to promote inflammation in the initial period post-injury, but at later stages, H2S reduces inflammation and improves wound healing in the burn model. Although this action has not yet been extensively studied, it is promising due to the potential therapeutic role of H2S for treating burns.
Many results indicate that H2S can improve wound healing due to its functions of stimulating angiogenesis and anti-inflammatory action. Therefore, enhancement of endogenous H2S synthesis or delivery of appropriate concentrations of H2S may have clinical utility in enhancing the healing of wounds, including gastrointestinal ulcers. As a gasotransmitter, H2S rapidly travels through cell membranes without utilizing specific transporters and exerts a host of biological effects on a variety of biological targets resulting in a variety of biological responses. Similarly to the other two gasotransmitters NO and CO, many of the biological responses to H2S follow a bell-shaped dose-response: the effects of H2S range from physiological, cytoprotective effects (which occur at low concentrations) to cytotoxic effects (which are generally only apparent at higher concentrations). So far, it is still limited to use H2S as therapeutic agent in clinic due to shortage of H2S donors to release H2S at required concentration controllably and consistently. Therefore, a donor to control the H2S release process and a system to control the levels of H2S in different systems in the body is required to ensure that the treatment of burns is not detrimental to other systems.
As such, in order to overcome the limitations of H2S used in skin dressing clinically, it is necessary to provide donors that can release H2S consistently and the form of a dressing that can be easily applied over a wound or area of skin.